It is known that accumulation of cholesterol in the vascular system is an etiologic factor in various diseases such as coronary heart disease. Atherosclerosis, among them, is a form of arteriosclerosis which is characterized by the deposition of lipids, particularly cholesterol esters, on the walls, and the resulting thickening, of medium- and large-sized arteries.
It has recently been made clear that the production of such cholesterol ester is catalyzed by acyl-CoA cholesterol acyltransferase (ACAT). Thus, the excessive accumulation of cholesterol ester on the arterial wall is related to an increase in the ACAT enzyme level. Therefore, it is thought that if the ACAT enzyme is successfully inhibited, the esterification reaction of cholesterol will be retarded and the development and progression of atheromatous lesions due to excessive accumulation of cholesterol ester on the arterial wall be successfully prevented.
On the other hand, cholesterol in diets is absorbed as unesterified cholesterol, esterified by the action of ACAT in the body and released into the bloodstream in the form of chylomicrons. Therefore, inhibition of ACAT would suppress not only absorption of dietary cholesterol from the intestinal tract but also reabsorption of the cholesterol released into the intestine.
GB-A-2 113 684 discloses a series of antiatherosclerotic agents which are certain substituted urea and thiourea compounds having ACAT-inhibiting activity.
EP-A-0 335 375 also discloses a series of antihyperlipidemic and antiatherosclerotic agents which are certain substituted urea compounds having ACAT-inhibiting activity.